8 Theauthors...havebeendoing... have an outstanding service in bringing the potential of these agents to the attention of the medical community in a convincing manner. It is likely that the first decade of the 21 st century will continue to be a time of great advances in the treatment of thrombotic disorders. Shapiro SS, NEJM; Editorial, October 30, 2003

9 Three Phases in the Evaluation of Antithrombotic Therapies in VTE and Evolution of Outcome Assessment First Phase 1938 late 1960 s Second Phase 1972 early 1990 s Third Phase

10 First Phase First use of heparin in 35 pts with VTE. Murray (1937) and Crafoord (1937) Heparin i.v. in 209 VTE pts with only 3 deaths. Bauer (1946) Heparin and Dicoumarol in 329 pts with one death. Allen et al (1947) Heparin i.v. and nicoumalone vs. no treatment randomized comparison in 35 PE pts. Barritt and Jordan (1960) Survival as major outcome

15 Second Phase Studies about the appropriate monitoring of APTT and INR, as well as the duration of initial therapy (1972 to early 1990 s) Symptomatic recurrent venous thromboembolism and major bleeding as major outcomes

16 Third Phase Studies with LMWH, pentasaccharides, thrombin inhibitors and factor Xa inhibitors. (1992 approx 2010) Out of hospital treatment, no laboratory monitoring, ease of use, non-inferiority for efficacy and clinically relevant/non major bleeding as major outcomes. No distinction between initial and long term treatment

17 The Tasman Study The Tasman Map, also known as the 'Bonaparte Map', made from information collated from voyages made by Abel Tasman between , 44, alongside information gathered by previous Dutch explorers in the region.

41 Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH) In patients with a first episode of PE the cumulative incidence of symptomatic CTEPH is 38%attwoyears 3.8% two All CTPEH developed within two years of the acute episode Risk factors for CTPEH were large perfusion defects, increased age, previous PE, or idiopathic PE Prevention of recurrent PE has potential to decrease incidence of CTPEH Pengo et al. NEJM, 2004

42 Remarkable progress has been made in understanding the etiology, prevalence, natural history, and therapeutic approach to chronic c thromboembolic pulmonary hypertension (CTEPH) during the past two decades. This disease, first described as an autopsy curiosity (Ball 1956, Carrol 1950, Chait 1967, Hollister 1956), results from obstruction of the major (main, lobar, segmental) pulmonary arteries with incompletely resolved or organized pulmonary emboli which have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistance.

43 Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

44 Pavia CTPH Program Surgical Specimens from Different Patients t

45 In the final analysis, the therapeutic efficacy of any drug can only be demonstrated by clinical trials in man Annotation, British Journal of Haematology 1984

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